Diuretics and Agents that affect water excretion; Electrolytes

Philip Marcus, MD MPH

Diuretics:

Increase output of urine - “diuresis”

Increase renal Na+ excretion - “natriuresis”

Clinical use of diuretics: Hypertension

Primary modality of treatment Forms base of treatment regimen

Mobilization of edema fluid Heart failure Liver disease (Cirrhosis) Renal disease

Prevention of renal failure (maintains urine flow)

Mechanism of Action Agents best understood in relation

to sites of action in the nephron. Each site of nephron highly specialized in function.

Almost all diuretics exert their effects at luminal surface of renal tubular cells. Ion transport inhibitors.

Mechanism of Action Diuretics compromise normal

operation of the kidney to promote excretion of water.

Diuretic use can result in:

Hypovolemia Acid-base imbalance Loss of electrolytes

Attempt to Minimize Adverse Effects By:

Short-acting diuretics

Time doses to allow drug-free periods between periods of diuresis. Will allow kidney to readjust ECF to

compensate for undesired alterations.

Diuretic-like Agents: Methylxanthines (caffeine,

theophylline), cardiac glycosides (digoxin) and sympathomimetic amines (dopamine) act at the level of the glomerulus to increase volume of blood filtered via increase in cardiac output.

Renal Function: Cleansing of extracellular fluid (ECF),

maintenance of ECF volume and composition.

Maintenance of acid-base balance.

Excretion of metabolic wastes and foreign substances (drugs, toxins, etc.).

Effects of the Kidney Upon ECF are Net Result of:

Filtration

Reabsorption

Active Secretion

The Nephron

Filtration: Glomerular level

1st step in urine formation

All small molecules filtered… Electrolytes, glucose, amino acids, Na+, K+,

Cl-, HCO3- -- most prevalent Large filtration capacity Nonselective…cannot regulate composition

of urine

Sites of Sodium Absorption

Reabsorption: > 99% of filtrate Conserves valuable portions while

allowing wastes to be excreted Reabsorption of solutes—active

transport H20 follows passively PRIMARY ACTION OF DIURETICS! Na+, K+ predominant solutes in filtrate

Active Secretion: Transports compounds from

plasma into lumen of nephron.

Located in PCT. Organic Acids (S2) – uric acid,

antibiotics. Organic Bases (S1 and S2) –

creatinine, choline, and procainamide.

The Nephron

Proximal ConvolutedTubule: High resorptive capacity.

65% of filtered Na+, Cl- reabsorbed.

Also HCO3-, K+, glucose, amino acids.

H2O follows passively.

Solutes and H2O reabsorbed to = extent… Urine is isotonic (300 mOsm/L).

Loop of Henle: Descending Limb:

Thin segment. Freely permeable to H20. As tubular urine moves down loop

thru hypertonic medulla, H2O is drawn from loop into interstitial space.

Will decrease volume of urine and increase concentration.

Loop of Henle: Ascending Limb:

Thick segment. NOT permeable to H2O 30% of filtered Na+ & Cl- reabsorbed (actively). H2O remains in loop as Na+ and Cl- reabsorbed -

tonicity returns to original. Regard as diluting segment. Utilizes Na+/K+/2Cl- cotransport system which is selectively blocked by diuretics. The action of the transporter lead to excess K+ accumulation within the cell.

Results in back diffusion of K+ into tubular lumen lumen + electrical potential.

Driving force for reabsorption of Mg+ and Ca+ via paracellular pathway.

Distal ConvolutedTubule: 10% of filtered NaCl reabsorbed.

H20 follows passively.

Na+ and Cl- neutral cotransport.

Ca+ actively reabsorbed via apical Ca+

channel and basolateral Na+/Ca++

exchanger regulated by PTH.

Collecting Tubule: 2-5% of NaCl reabsorption. Responsible for determining final concentration

of Na+ in urine. Na+/K+exchange…

ALDOSTERONE increases activity of apical membrane channels and basolateral Na+/K+ ATPase.

Major site of K+ excretion. Impermeable to H2O in absence of ADH…dilute

urine produced. Only site in nephron where membrane H2O

permeability can be regulated. ADH increases permeability to H2O

Action of Diuretics: Blockade of Na+ (and Cl-) reabsorption Create osmotic pressure within nephron

that prevents passive reabsorption of H2O CAUSE H2O & SOLUTES TO BE RETAINED

WITHIN THE NEPHRON Thereby PROMOTING THEIR EXCRETION

The increase in urine flow that a diuretic produces is directly related to the amount of Na+ and Cl- reabsorption that the drug blocks

Sites of Sodium Absorption

Drugs Whose Site of Action Is Early in the Nephron Will Have the Opportunity to Block the Greatest of Solute Reabsorption…Produce Greatest Diuresis.

180 L Filtrate/day…almost all reabsorbed.

For each 1% of solute reabsorption blocked, urine output increases by 1.8 L

3% blockade = 5.4 L urine/day = 12 lb. weight loss.

Small blockade can have profound effects.

Classification

Loop (High-ceiling) diuretics Thiazide diuretics Osmotic diuretics Potassium-sparing diuretics

Aldosterone antagonists Inhibitors of Na+ transport

Carbonic anhydrase inhibitors Mercurial diuretics

Actions of Diuretic Agents: Inhibition of specific membrane

transport proteins at luminal surface of renal tubular epithelial cells.

Osmotic effect to prevent water reabsorption in water – permeable segments.

Enzyme inhibition. Interfere with hormone receptors in

renal epithelial cells.

Loop (High-Ceiling) Diuretics GREATEST EFFICACY – Cause large

increase in fractional excretion of Na+

Furosemide (Lasix®) Bumetanide (Bumex®) Ethacrynic Acid (Edecrin®) Torsemide (Demadex®)

Loop Diuretics

Loop (High-Ceiling) Diuretics Act to inhibit coupled Na+/K+/2Cl- transport

system in luminal membrane of thick ascending limb of loop of Henle

Blocks Cl- and Na+ reabsorption and prevents passive H2O reabsorption

Normally up to 30% of filtered NaCl reabsorbed in ascending limb

Also diminishes normal lumen-positive potential that drives K+ recycling

Causes increase in Mg++ and Ca++ excretion Transport system driven by Na+/K+ ATPase

dependent pump

Pharmacokinetics: Rapidly absorbed. Response correlates with urinary excretion

rate. Eliminated by renal secretion and filtration. Action may be slowed by probenecid. Duration of action -- 2 or more hours. IV use for rapid effect. Hepatic metabolism. t 1/2 dependent on renal function.

Clinical Indications: Rapid or massive fluid mobilization

Pulmonary edema Acts to decrease LVEDP and decrease pulmonary vascular

congestion Edematous states

CHF Cirrhosis Nephrosis

Hypertension Hypercalcemia Acute renal failure

Convert oliguric to non-oliguric renal failure Anion overdose

Inhibits reabsorption of Br- , F-

Adverse Effects: Dehydration Hypotension Electrolyte Imbalance

Hyponatremia Hypochloremia HYPOKALEMIA Hypocalcemia Hypomagnesemia

Hyperglycemia Hyperuricemia Ototoxicity Cross reactivity in patients with SULFA allergy

Ethacrynic acid in phenoxyacetic acid derivative

Thiazide Diuretics(Benzothiadiazides): All have unsubstituted sulfonamide group. Similar effects as loop diuretics…less

efficacy. *Hydrochlorothiazide (HydroDIURIL®) Chlorothiazide (DIURIL®) Diazoxide—non-diuretic thiazide Chlorthalidone (Hygroton®) Indapamide (Lozol®) Metolazone (Zaroxolyn®, Mykrox®)

Thiazide Diuretics

Thiazide Diuretics: Act to inhibit NaCl reabsorption from

luminal side of epithelial cells in DCT (early segment).

Bind to Cl- site of electroneutral Na+/Cl- cotransport system.

No effect on loop of Henle.

Enhance Ca+2 reabsorption in DCT.

Efficacy vs. Potency

Clinical Indications: Hypertension

Drug of choice for initial therapy of hypertension

CHF Hypercalciuria, nephrolithiasis Nephrogenic Diabetes Insipidus

reduces polyuria and polydipsia where no

response to ADH Seemingly paradoxical effect

Adverse Effects: Most Similar To Those Of Loop Diuretics

Hypercalcemia

Hyperlipidemia {5-15% in cholesterol (LDL)}.

No Ototoxicity.

Hyperglycemia

Potassium-Sparing Diuretics:

Cause mild to moderate increase in urine production

Substantial decrease in K+ excretion.

Rarely employed to promote diuresis.

Potassium-Sparing Diuretics

Spironolactone (Aldactone®) Blocks action of aldosterone via direct competitive

antagonism at level of cytoplasmic mineralocorticoid receptors in distal nephron (DCT + CT). Spironolactone-receptor complex does not attach to DNA. Prevents translocation of receptor complex to nucleus. Aldosterone acts to promote Na+ uptake in exchange for K+ secretion… see Na+ loss and K+ sparing…mild diuretic effect…most Na+ already reabsorbed by more proximal nephron.

Slow onset of action Need to exhaust proteins already formed by aldosterone

action…1-2 days. Well absorbed from GI tract. t ½ =10 minutes Active metabolite canrenone has t ½ = 16 hours.

Cellular Action of Aldosterone

Spironolactone (Aldactone®) Useful primarily in states of aldosterone

excess associated with diminished effective extracellular volume

CHF Cirrhosis Nephrotic syndrome

Adverse Effects HYPERKALEMIA

Increased risk with renal disease, drugs which decrease renin (-blocker, NSAID) or ACE inhibitor

Hyperchloremic metabolic acidosis Inhibits H+ secretion along with K+ secretion

Gynecomastia, impotence

Eplerenone (Inspra®) Blocks binding of aldosterone to

mineralocorticoid receptor Selective binding compared to

glucocorticoid, progesterone and androgen receptors

Produces sustained increases in plasma renin and serum aldosterone Consistent with negative regulatory

feedback of aldosterone on renin secretion Resultant increased renin activity and

circulating aldosterone do not overcome effects of eplerenone on BP

Eplerenone (Inspra®) Peak concentrations in 1.5 hours 50% plasma protein binding Metabolism via CYP3A4

Inhibitors of CYP3A4 will raise blood levels of eplerenone

Ketoconazole Saquinavir Erythromycin fluconazole

t ½ = 4-6 hours

Eplerenone (Inspra®) Hyperkalemia principal risk Increased risk of hyperkalemia with

ACE inhibitors Angiotensin Receptor Blockers

Well tolerated Indications:

HYPERTENSION Improvement of survival post MI in patients

with evidence of LV systolic dysfunction (EF ≤ 40%)

Introduced: Sept. 2002 15% Reduction in all-cause mortality

Triamterene (Dyrenium®): Influences Na+-K+ exchange in distal

nephron.

Direct inhibitory effect.

No effect on aldosterone.

Acts within few hours.

Limited diuretic efficacy.

Metabolized in liver. Short t1/2. Well absorbed.

Clinical Indications: Hypertension Mild edema Usually combined with another diuretic:

+hydrochlorothiazide = Dyazide® Also, AMILORIDE (Midamor®)-

blocks luminal Na+ channels by which aldosterone produces main effect. Poorly absorbed, slower onset of action, peak 6 hours.

+ hydrochlorothiazide = Moduretic®

Carbonic Anhydrase Inhibitors:

Carbonic anhydrase present in luminal and basolateral membranes, epithelial cell cytoplasm, and RBC’s. Luminal membrane of PCT predominant site.

Catalyzes dehydration of H2CO3…critical step in HCO3 reabsorption. CO2 + OH- HCO3-

Inhibition of Carbonic Anhydrase causes diuresis and reduction in total body HCO3 stores.

Depresses HCO3 reabsorption. HCO3 accumulates in luminal fluid.

Carbonic Anhydrase Inhibitors: Forerunners of modern diuretics.

Sulfonamides [-SO2NH2] noted to cause hyperchloremic, metabolic acidosis with large volumes of alkaline urine.

Thiazides developed to separate natriuretic effects from effects of HCO3 handling.

Carbonic Anhydrase Inhibitors: Acetazolamide (Diamox®) Dichlorphenamide (Daranide®) Methazolamide (Neptazane®) Dorzolamide (Trusopt®)

SO2NH2 Group is essential for activity 85% of HCO3 resorptive activity is inhibited

in PCT. 45% of whole kidney HCO3 reabsorption is

inhibited.

Carbonic Anhydrase Inhibitors

Clinical Actions: Increases urine volume Alkaline pH of urine Increases HCO3

-, K+, Na+ in urine Decreases Cl- in urine Decreases HCO3- in blood: metabolic

acidosis Hypokalemia HCO3- depletion; enhanced NaCl

reabsorption by remaining nephron segments; loss of effectiveness within days.

Carbonic Anhydrase Inhibitors: Carbonic anhydrase also present in

ciliary body and choroid plexus. Aqueous humor and CSF formation are HCO3- dependent. Processes are in opposite direction from that in PCT. Both are able to be inhibited and pH and quantity of fluid formed will be affected.

Pharmacokinetics: Well absorbed after oral

administration.

Increase in urine pH within ½ hour; maximal in 2 hours.

Excretion by tubular secretion in S2 segment.

Clinical Indications: Glaucoma-Inhibition of CA decreases

rate of aqueous humor formation and decreases IOP.

Urinary alkalinization-uric acid, cystine relatively insoluble in acid urine. Excretion of weak acids (aspirin) enhanced in alkaline urine.

Reduction of total body HCO3- stores. Acute mountain sickness. Absence seizures.

Toxicity: Hyperchloremic metabolic acidosis. Hypokalemia. Renal stones - Ca++ salts relatively

insoluble in alkaline urine. HCO3- loss in

urine results also in phosphaturia and hypercalciuria.

CONTRAINDICATED in cirrhosis. Urinary alkalinization results in decreased excretion of NH4

+.

Osmotic Diuretics: Mannitol

Freely filtered. Minimal reabsorption. Not metabolized. Pharmacologically inert. Given in amounts large enough to constitute

appreciable fraction of plasma osmolarity.

Also, Urea and Glycerin

Osmotic Diuretics: Creates osmotic force within lumen of

nephron prevents H2O reabsorption in those segments freely permeable to H2O (PCT and descending loop of Henle).

Degree of diuresis related to amount of mannitol in filtrate. Little effect on loss of K+. Does not produce diuretic effects by blocking reabsorption of Na+ or Cl-.

IV use only. Cannot diffuse across GI epithelium.

Osmotic Diuretics: Clinical Indications: Prophylaxis of renal shutdown.

- Increases Urine volume. Reduction of intracranial or intraocular

pressure.

Adverse Effects: Volume expansion. Dehydration, hypernatremia.

Agents that Affect Water Excretion: ADH (VASOPRESSIN): Acts at collecting

tubule to modulate concentration of final urine.

Secretion during hypotonic volume expansion large volumes of dilute urine formed.

Secretion during volume contraction & hypertonic conditions urine concentration by water abstraction.

Thick ascending limb of loop of Henle plays central role during concentration and dilution of urine.

ADH = Antidiuretic + Vasopressor Effects:

Vasopressin-nonapeptide…arginine @ position 8.

Primarily parenteral administration—IV, IM, intranasal. t1/2 = 20 minutes Renal and hepatic catabolism Reduction of disulfide bond + peptide cleavage.

Receptors: V1 mediate vasoconstriction.

V2 (Renal) mediate antidiuresis through H2O permeability and H2O resorption in CT and CD.

V2 (Extrarenal) mediate release of Factor VIIIc and von Willebrand Factor as well as BP and SVR.

ADH Antagonists: Li+ salts, demeclocycline inhibit

effects of ADH at collecting tubule via adenylyl cyclase and at some step following cAMP generation by ADH…effects of cAMP antagonized.

Preparations: Aqueous Vasopressin (Pitressin®)

Short acting IV, IM, or SQ Q 3-6 hours Lysine Vasopressin (Diapid®)

Short-acting nasal spray Q 4-6 hours Desmopressin (DDAVP®)

1-desamino-8-D-arginine vasopressin. Long-acting synthetic analogue of vasopressin…minimal

V1 activity. Antidiuretic: pressor = 4000 x vasopressin. Most expensive. Preferred for chronic therapy. Nasal spray, nasal tube, IV, SQ, or po Q 8-12 hours.

ADH Agonists: USE:

Diabetes Insipidus (Pituitary): Vasopressin Nocturnal Enuresis: DDAVP GI Bleeding: Vasopressin infusion Assess renal concentrating ability after long-

term lithium therapy: DDAVP Coagulopathy (Hemophilia A, von Willebrand’s):

DDAVP TOXICITY:

Headaches, nausea, cramps Caution: Nasal congestion

Electrolyte Replacement Therapy

Potassium Sodium Magnesium Phosphate Bicarbonate

Potassium Replacement Products

Potassium gluconate Potassium citrate Potassium bicarbonate Potassium acetate Potassium chloride

mEq/g of various Potassium Salts

Potassium Salt mEq/g

Potassium gluconate 4.3

Potassium citrate 9.8

Potassium bicarbonate

10

Potassium acetate 10.2

Potassium chloride

13.4

Potassium Chloride: Oral Forms

Controlled Release tablets 8 mEq (600 mg); 6.7 mEq (500 mg)

Controlled Release capsules 10 mEq (750 mg)

Liquid 20 mEq/15 ml ( 1500 mg) 30 mEq/15 ml (2250 mg) 40 mEq/15 ml ( 3000 mg)

Potassium Chloride: IV Use Generally prepared in

concentrated form 2mEq/ml 10mEq in 5ml,10ml, 50ml and 100ml

vials 20mEq in 10ml and 20 ml vials

Concentrate MUST me diluted before use

Potassium administration:Guidelines

Serum K+Maximum Infusion

Rate

Maximum Concentratio

n

Maximum 24 hour

dose

>2.5mEq/L 10 mEq/hr 40 mEq/L 200 mEq

< 2 mEq/L 40 mEq/hr 80 mEq/L 400 mEq

Intravenous Fluids NaCl (Saline)

0.9% (Normal Saline) 0.3% 0.33% 0.45% (½ normal saline) 3% (Hypertonic saline)

Ringer’s Injection (Solution) 310 mOsm/L Na, K, Ca, Cl

Lactated Ringer’s Injection Na, K, Ca, Cl, lactate 274 mOsm/L

All available with or without

Dextrose (5%)

Dextrose available without

electrolytes:

D5W, D10W

Magnesium Sulfate (MgSO4) Treatment of

hypomagnesemia Seizure prevention in

eclampsia and pre-eclampsia Treatment of cardiac

arrhythmias Hypomagnesemia Torsades de pointes

Constipation Soft-tissue injuries Status asthmaticus

Epsom Salts

Magnesium Sulfate (MgSO4) Routes of Administration

IV IM Oral Topical

Magnesium content 10% elemental Mg 8.1 mEq/g